タブンによってリン酸化されたコレニステラゼの老化は,O-脱アルキル化によって進行する

Eugénie Carletti¹, He Li, Bin Li

¹Département de Toxicologie, Centre de Recherches du Service de Santé des Armées, 38700 La Tronche, France.

Journal of the American Chemical Society

|November 4, 2008

まとめ

人間のブチリルコリンエステラゼ (hBChE) は,有毒エステルから保護します. タブン抑制酵素の老化はオキシーム耐性を引き起こしますが,構造データは新しい活性化器の設計を導くことができます.

科学分野:

バイオケミストリーバイオケミストリー
構造生物学構造生物学とは
毒理学毒理学毒理学

背景:

ヒューマンブチリルコリンエステラーゼ (hBChE) は,農薬や神経毒剤を含む様々な有害なエステルから排毒します.
オルガノフォスファート (OPs) は,リン酸化経由でアセチルコレネステラーゼ (AChE) と関連するコレネステラーゼ (ChEs) を阻害し,老化後の不可逆的な抑制につながります.
タブン-ChE結合体はオキシーム活性化に抵抗性があり,大きな課題となっています.

研究の目的:

タブン抑制されたCHE結合体におけるオキシム抵抗性の構造的基礎を解明する.
タブン-hBChEとタブン-mAChEの老化メカニズムを理解するために.

主な方法:

未老化および老化したタブン抑制 hBChE.E.の結晶構造の決定.
タブン抑制マウスACHE (mAChE) の未老化および老化した精製された結晶構造.
タブン製の老化抑制されたhBChE.の質量スペクトロメトリック分析を行った.

主要な成果:

結晶構造は,タブンP (R) エナンチオメアのO-デアルキル化による老化過程を明らかにした.
脱基化酸素と陽子化His438の間に塩の橋が形成され,再活性化を阻害する.
質量スペクトロメトリーは,リン原子からエトキシとダイメチラミン側鎖の喪失を確認した.

結論:

構造および質量スペクトロメトリのデータは,老化したタブン-ChE結合物のオキシム再活性化に対する耐性を説明します.
これらの発見は,タブン誘発のChE阻害を克服するために新しいオキシメスを設計するための基礎を提供します.

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